title: CD52 as a molecular target for immunotherapy to treat acute myeloid leukemia with high EVI1 expression.
abstract: Ecotropic viral integration site 1 (EVI1) is an oncogenic transcription factor in human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. Because a high expression of EVI1 protein in AML cells predicts resistance to chemotherapy with a poor outcome, we have searched for molecular targets that will treat these patients with AML. In this study, we determined that CD52, which is mainly expressed on lymphocytes, is highly expressed in most cases of AML with a high EVI1 expression (EVI1(High)). CAMPATH-1H, a humanized monoclonal antibody against CD52, has been used to prevent graft-versus-host disease and treat CD52-positive lymphoproliferative disorders. Here, we investigated the antitumor effect of CAMPATH-1H on EVI1(High) AML cells. CAMPATH-1H significantly inhibited cell growth and induced apoptosis in CD52-positive EVI1(High) leukemia cells. Furthermore, CAMPATH-1H induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against CD52-positive EVI1(High) leukemia cells. After an intravenous injection of CAMPATH-1H into NOD/Shi-scid/IL-2Rγ;null mice with subcutaneous engraftment of EVI1(High) leukemia cells, tumor growth rates were significantly reduced, and the mice survived longer than those in the phosphate-buffered saline-injected control group. Thus, CAMPATH-1H is a potential therapeutic antibody for the treatment of patients with EVI1(High) leukemia.
authors.affiliation: Department of Medical Science, Division of Tumor and Cellular Biochemistry, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: S
authors.initials: S
authors.lastname: Nakahata
authors.forename: N
authors.initials: N
authors.lastname: Yamakawa
authors.forename: K
authors.initials: K
authors.lastname: Kaneda
authors.forename: E
authors.initials: E
authors.lastname: Ichihara
authors.forename: A
authors.initials: A
authors.lastname: Suekane
authors.forename: K
authors.initials: K
authors.lastname: Morishita
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis*; D000951:Antigens, Neoplasm / Q000032:analysis*; D000074301:CD52 Antigen; D004268:DNA-Binding Proteins / Q000032:analysis*; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000032:analysis*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors